Androgens are a major stimulator of prostate tumor growth and all current therapies act as classic antagonists by competing with androgens for binding the androgen receptor (AR) hormone binding pocket. This mechanism of action exploits the dependence of AR for hormone activation and current treatment options are essentially ineffective once androgen-dependence is lost. Thus, drugs that target novel surfaces on AR and/or novel AR regulatory mechanisms are promising additions for the treatment of hormone refractory prostate cancer. Both FKBP52 and β-catenin have emerged in recent years as attractive therapeutic targets. The compound MJC13 is a first-in-class drug for targeting the regulation of AR by FKBP52. Through binding a recently identified regulatory surface on AR (BF3), MJC13 prevents the FKBP52-receptor complex from dissociating resulting in the retention of AR in the cytoplasm (De Leon et al. (2011) Proc Natl Acad Sci USA 108:11878-83). MJC13 was shown to effectively block AR signaling and AR-dependent cancer cell proliferation in a variety of human prostate cancer cell lines, and preclinical studies demonstrate impressive effects on tumor growth in a prostate cancer xenograft model (Liang et al., (2014) Pharm Dev Technol, 1-6; Liang et al. (2014) American Journal of Modern Chromatography 1:1-11).
For comparison, other the antiandrogen drugs act as classic anti-androgens through binding the hormone binding pocket. Some antiandrogens prevents AR from entering the nucleus of the cell. This unique mechanism of action has propelled some antiandrogens to the forefront of the prostate cancer drug market in a very short period of time. MJC13 also prevents AR from entering the nucleus. However, MJC13 is unique in that it targets an alternative surface on AR. This “indirect AR targeting” should bypass the partial agonistic effects that result from targeting the hormone binding pocket. In addition, targeting this alternative surface should not be affected by disease resistance to antiandrogens. Thus, MJC13 offers both the positive properties of inhibiting nuclear translocation and prevention of undesirable side effects associated with targeting the AR hormone binding pocket.